John Muir Medical Center

IntroductionIndividuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.MethodsWe genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.ResultsWe discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.ConclusionsThis study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0567-2) contains supplementary material, which is available to authorized users.

Sexual assault is a major cause of injury, unplanned pregnancy, HIV infection, and mental health problems worldwide. In parts of sub-Saharan Africa, sexual assault has reached epidemic proportions. This study evaluated the efficacy of an empowerment and self-defense intervention for adolescent girls to decrease the incidence of sexual assault and harassment in Nairobi's large informal settlements. A prospective cohort of 1978 adolescents from 4 neighborhoods near Nairobi were taught empowerment, deescalation, and self-defense skills in six 2-hour sessions. The standard-of-care (SOC) group (n = 428) received a life skills class. Self-reported, anonymous survey data were collected at baseline and 10.5 months after intervention. Annual sexual assault rates decreased from 17.9/100 person-years at baseline to 11.1 at follow-up (rate ratio = 1.61; 95% confidence interval [CI], 1.26-1.86; P < .001); there was no significant change in the SOC group (14.3 to 14.0, rate ratio = 1.02; 95% CI, 0.67-1.57, P = .92). Sexual assault disclosure in the intervention group increased from 56% to 75% (P = .006), compared with a constant incidence of disclosure (53%) in the SOC group. The majority (52.3%) of adolescents in the intervention group reported using skills learned to stop an assault. This intervention decreased sexual assault rates among adolescent girls in Kenya. The intervention was also associated with an increase in the disclosure of assaults, thereby enabling survivors to seek care and support and possibly leading to the identification and prosecution of perpetrators. This model should be adaptable to other settings both in Africa and globally.

To assess in a headache clinic population the relationship of childhood abuse and neglect with migraine characteristics, including type, frequency, disability, allodynia, and age of migraine onset. Childhood maltreatment is highly prevalent and has been associated with recurrent headache. Maltreatment is associated with many of the same risk factors for migraine chronification, including depression and anxiety, female sex, substance abuse, and obesity. Electronic surveys were completed by patients seeking treatment in headache clinics at 11 centers across the United States and Canada. Physician-determined data for all participants included the primary headache diagnoses based on the International Classification of Headache Disorders-2 criteria, average monthly headache frequency, whether headaches transformed from episodic to chronic, and if headaches were continuous. Analysis includes all persons with migraine with aura, and migraine without aura. Questionnaire collected information on demographics, social history, age at onset of headaches, migraine-associated allodynic symptoms, headache-related disability (The Headache Impact Test-6), current depression (The Patient Health Questionnaire-9), and current anxiety (The Beck Anxiety Inventory). History and severity of childhood (<18 years) abuse (sexual, emotional, and physical) and neglect (emotional and physical) was gathered using the Childhood Trauma Questionnaire. A total of 1348 migraineurs (88% women) were included (mean age 41 years). Diagnosis of migraine with aura was recorded in 40% and chronic headache (>or=15 days/month) was reported by 34%. Transformation from episodic to chronic was reported by 26%. Prevalence of current depression was 28% and anxiety was 56%. Childhood maltreatment was reported as follows: physical abuse 21%, sexual abuse 25%, emotional abuse 38%, physical neglect 22%, and emotional neglect 38%. In univariate analyses, physical abuse and emotional abuse and neglect were significantly associated with chronic migraine and transformed migraine. Emotional abuse was also associated with continuous daily headache, severe headache-related disability, and migraine-associated allodynia. After adjusting for sociodemographic factors and current depression and anxiety, there remained an association between emotional abuse in childhood and both chronic (odds ratio [OR] = 1.77, 95% confidence intervals [CI]: 1.19-2.62) and transformed migraine (OR = 1.89, 95% CI: 1.25-2.85). Childhood emotional abuse was also associated with younger median age of headache onset (16 years vs 19 years, P = .0002). Our findings suggest that physical abuse, emotional abuse, and emotional neglect may be risk factors for development of chronic headache, including transformed migraine. The association of maltreatment and headache frequency appears to be independent of depression and anxiety, which are related to both childhood abuse and chronic daily headache. The finding that emotional abuse was associated with an earlier age of migraine onset may have implications for the role of stress responses in migraine pathophysiology.